title: Toll-like receptor 3 (TLR3) induces apoptosis via death receptors and mitochondria by up-regulating the transactivating p63 isoform alpha (TAP63alpha).
abstract: Toll-like receptor 3 (TLR3), a member of the pathogen recognition receptors, is widely expressed in various cells and has been shown to activate immune signaling pathways by recognizing viral double-stranded RNA. Recently, it was reported that the activation of TLR3 induced apoptosis in some cells, but the detailed molecular mechanism is not fully understood. In this study, we found that in endothelial cells polyinosinic-polycytidylic acid (poly(I-C)) induced dose- and time-dependent cell apoptosis, which was elicited by TLR3 activation, as TLR3 neutralization and down-regulation repressed the apoptosis. Poly(I-C) induced the activation of both caspases 8 and 9, indicating that TLR3 triggered the signaling of both the extrinsic and intrinsic apoptotic pathways. Poly(I-C) up-regulated tumor necrosis factor-related apoptosis-inducing ligand and its receptors, death receptors 4/5, resulting in initiating the extrinsic pathway. Furthermore, poly(I-C) down-regulated anti-apoptotic protein, B cell lymphoma 2 (Bcl-2), and up-regulated Noxa, a key Bcl-2 homology 3-only antagonist of Bcl-2, leading to the priming of the intrinsic pathway. A p53-related protein, the transactivating p63 isoform α (TAp63α), was induced by TLR3 activation and contributed to the activation of both the intrinsic and extrinsic apoptotic pathways. Both the cells deficient in p63 gene expression by RNA interference and cells that overexpressed the N-terminally truncated p63 isoform α (ΔNp63α), a dominant-negative variant of TAp63α, by gene transfection, survived TLR3 activation. Taken together, TAp63α is a crucial regulator downstream of TLR3 to induce cell death via death receptors and mitochondria.
authors.affiliation: Central Laboratory, Renmin Hospital, Wuhan University, Wuhan, China.
authors.forename: Ruili
authors.initials: R
authors.lastname: Sun
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Lv
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Miao
authors.initials: M
authors.lastname: Jin
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Minjie
authors.initials: M
authors.lastname: Deng
authors.forename: Xueting
authors.initials: X
authors.lastname: Liu
authors.forename: Guancheng
authors.initials: G
authors.lastname: Li
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Li
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhou
authors.forename: Pingli
authors.initials: P
authors.lastname: Xie
authors.forename: Xiumei
authors.initials: X
authors.lastname: Xie
authors.forename: Jinyue
authors.initials: J
authors.lastname: Hu
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Duan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D020033:Protein Isoforms; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C495344:TLR3 protein, human; C105190:TNFRSF10A protein, human; C115051:TP63 protein, human; D051196:Toll-Like Receptor 3; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011070:Poly I-C